Kumaresan and Seneviratne Globalization and Health (2017) 13:43 DOI 10.1186/s12992-017-0268-y

COMMENTARY Open Access Beginning of a journey: unraveling the mystery of of unknown aetiology (CKDu) in Jacob Kumaresan1* and Ruwanika Seneviratne2

Abstract Background: Globally, chronic kidney disease of unknown aetiology (CKDu) is observed in several areas and among specific ethnic or occupational groups. Given the widespread environmental pollution and the proportions of agriculture workers world-wide, CKDu may be the next global public health issue demanding attention. Recent escalation of CKDu in Sri Lanka has caused a serious public health crisis in the country, made worse by lack of national data. Main text: The specific geographic distribution, preponderance among farming population, similar histology findings and absence of usual risk factors for kidney disease indicate undetected nephrotoxic agents playing a role in causation. Some of the challenges for the country are uncoordinated preventive efforts, diverse opinions among stakeholders on causality and fragmented research efforts with limited focus on potential causes of CKDu. As a result, accurate estimation of the CKDu burden, identification of causative agents and implementation of effective actions have been delayed. Stakeholder engagement, with involvement of international experts has been the starting point for finalizing a working case definition to establish community based surveillance as a future platform to conduct long-term research. Conclusion: The country is now poised to contribute to global knowledge by solving the mystery of ‘u’ in CKDu. This commentary highlights the importance and the mechanisms of making an effective breakthrough as early as possible; failing which CKDu can progress rapidly as demonstrated by the situation in Sri Lanka. Keywords: CKDu, Research, Surveillance of chronic kidney disease

Background factors; indicate the likelihood of one or more yet The escalation of chronic kidney disease of unknown undetected nephrotoxic environmental agents playing a aetiology (CKDu) in Sri Lanka, which emerged in the early role in causation [1, 2]. 1990s, has caused a serious public health crisis in the Globally, a similar scenario is observed with rise in country [1]. In Sri Lanka, non-communicable diseases CKD ‘hotspots’ either in specific geographical regions (NCDs) and problems related to old age are rapidly or among specific ethnic or occupational groups. increasing due to the epidemiological and demographic -related nephropathy in Japan, Balkan en- transitions. High life expectancy at birth and prevalence of demic nephropathy in countries around the Danube and have resulted in conditions river basin, Uddanam endemic nephropathy in India such as Chronic Kidney Disease (CKD). However, the and Mesoamerican nephropathy among sugar cane recent emergence of a particular form of CKD with similar cutters are some of the key endemic nephropathies histology, in a specific geographic location, commonly reported in literature [3, 4] . In some areas, the causes within the farming population, in the absence of usual risk have been identified whereas in other areas including Sri Lanka, the aetiology remains unknown. * Correspondence: [email protected] The current disease surveillance system of the country 1World Health Organization Country Representative to Sri Lanka, No 05, Anderson Road, Colombo 05, Sri Lanka does not provide accurate estimation of the disease Full list of author information is available at the end of the article burden on a national scale. Due to the lack of national

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registries and limited reporting of non-communicable Patients range in age from 17–70 but are most com- diseases, the prevalence of CKDu in Sri Lanka is not monly men aged 30–60 [2]. known [5]. A number of studies report prevalence for In another study, population surveys were carried out in geographical regions. As the study populations and case three different provinces in Sri Lanka. Medawachchiya, definitions vary widely caution needs to be exercised in located in NCP; Yatinuwara, located in the Central Prov- interpreting findings. ince (CP); and Hambanthota in the Southern Province Although several aetiological studies, including labora- (SP) were sampled (n = 6153, 87% response rate) [5]. In tory, environmental and population studies have been the regions selected in the NCP, 84% had patients with conducted in Sri Lanka, there are many gaps in litera- CKDu, compared with CP which reported 2.9% and SP ture due to limited focus on potential risk factors and which had 9.1% [5]. inadequate samples [5–7]. In Sri Lanka, histo-pathological samples demonstrate Primary prevention, early diagnosis and multi- tubulo-interstitial disease which indicate toxic nephropa- stakeholder engagement for action are some cost-effective thy pointing to environmental agents playing a role in options available for a low-middle income country like Sri pathogenesis [2, 5, 10]. Factors implicated are pesticides Lanka to tackle this problem. However, with different such as organophosphates; Hantavirus; fungal toxins; views being held by the scientific communities in the alcohol consumption; due to agrochemical country, opinions remain divided. Health authorities are use; dry, humid climate and consumption. It now attempting to streamline research activities and is postulated that several agents and genetic predispos- establish surveillance of CKDu with the involvement of all ition may play a role in causation [1, 2, 10]. relevant stakeholders. The objective of this article is to The country faces many challenges due to the ‘epidemic’ present how, as a developing low-middle income country of CKDu. Continuing the provision of free-healthcare with restricted resources, Sri Lanka is addressing this services to those with CKDu is a major concern. The bur- unique challenge. den due to CKDu continues to increase and, in the absence of knowledge on causative agents the country has not yet Endemic nephropathy in Sri Lanka- CKDu been able to make tangible progress in the prevention and Sri Lanka, with a population of over 20 million has com- control of CKDu. Challenges are identifying clear uniform mendable health services with indices on par with devel- criteria for population screening, providing long term care oped countries, achieved through comparatively low free-of-charge and preventing the younger generations resources [8]. This success has been attributed mainly to from exposure to the possible causative agents. In order to free healthcare and education policies since 1920s. The overcome these challenges health system strengthening, economic burden due to CKDu is significant with 4.6% and reforms to address the growing burden of non- of the Annual Health Budget in 2010 [9] being spent on communicable diseases have been identified. This includes managing patients. The free public service financing and revisiting the roles and responsibilities of the struggles to cater to the rising demand of chronic health workforce in the country. With this background, the ailments including renal replacement therapy. With over need for a systematic national approach to address CKDu 70,000 estimated patients with renal diseases, this is a becomes an important turning point in the planned health national priority needing urgent attention [2]. reforms. Chronic kidney disease of unknown etiology (CKDu) is CKD without diabetes, hypertension, preexisting renal conditions, or snake bite. It is slowly progressive, irre- National approaches to addressing CKDu versible, and asymptomatic until late stages [2]. In Sri The starting point for addressing CKDu was identifying Lanka, CKDu is observed more commonly in the North and setting up a multi stakeholder group focused on Central Province (NCP), of the dry zone, located in the advancing prevention and control of CKDu. To provide fluoride belt: it is populated with farming communities oversight and coordinate efforts, a Presidential Task which rely heavily on agrochemicals [1, 6]. CKDu primar- Force (PTF) on CKDu was set up in 2014 bringing much ily affects paddy farmers living in these areas [1, 7, 10], needed political backing and funding for CKDu from the the exact cause/s of which is still unclear despite more national budget. than 20 years of research. A population prevalence study In 2016, WHO and PTF convened an international conducted among 4957 participants from three endemic expert consultation, with national and international districts of NCP in 2010 and 2011 showed an age- experts, to guide future direction for addressing CKDu standardized prevalence of 12.9% (95% confidence inter- in Sri Lanka. Development of a robust surveillance val [CI]; 11.5%–14.4%) in males and 16.9% (95% CI; system; conduction of interdisciplinary research; strength- 15.5%–18.3%) in females. Males (23.2%) had the more ening implementation of interventions; provision of social severe form of the disease compared to females (7.4%). support to patients, family and community; and, developing Kumaresan and Seneviratne Globalization and Health (2017) 13:43 Page 3 of 4

a framework for monitoring and accountability were key of a more coordinated approach at national level, engaging recommendations from this consultation. all stakeholders and involving the global scientific A holistic National Action Plan 2016–2020 was devel- community will cutback limited resources spent on oped by PTF based on recommendations of the inter- fragmented and futile efforts and ultimately save lives. national consultation, with an overall goal of curbing the Abbreviations epidemic by understanding the aetiology of the problem. CKDu: Chronic kidney disease of unknown aetiology; NCD: Non-communicable Interim targets are provision of safe water to alleviate diseases; NCP: North Central Province; PTF: Presidential Task Force; WHO: World suffering of affected persons and their families; education Health Organization on prevention of illness/progression of disease; inter- Acknowledgements sectoral collaboration among various partners on inter- Not applicable. vention strategies; multifaceted research to determine causal factors; and, targeted communication to the Funding Not applicable. communities. The ministries of Health; Agriculture and Social Empowerment & Welfare will be the key partners Availability of data and materials involved in implementation of specific tasks. In addition, Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. National Water Supply & Drainage Board and the minis- tries of Finance; Education; Mass media; and Academia, Authors’ contributions along with civil societies and United Nations (UN) JK and RS conceptualized the design and the manuscript of this commentary. RS was involved in drafting the manuscript. JK revised the partners will be involved. document critically for content. Both authors read and approved the A standardized, uniform case definition was also final manuscript and are responsible for the final content. developed with the consensus of nephrologists, physicians, clinical and non-medical researchers, epidemiologists, Competing interests The authors declare that they have no competing interests. programme managers at national and district levels. The Ministry of Health has now embarked on community- Consent for publication based surveillance with the intention of generating Personal details of participants including images were not used. national data and for conducting long-term research on Ethics approval and consent to participate potential causative factors. Funding sources are the Not applicable and information was not collected from individuals. Government and the National Science Foundation. Publisher’sNote Conclusions Springer Nature remains neutral with regard to jurisdictional claims in Epidemiological and demographic transitions favouring a published maps and institutional affiliations. rise in NCDs, along with high usage of agrochemicals Author details and widespread environmental pollution can cause con- 1World Health Organization Country Representative to Sri Lanka, No 05, 2 ditions such as CKDu, a threat which many countries Anderson Road, Colombo 05, Sri Lanka. Ministry of Health, Nutrition and Indigenous Medicine, No 385, Rev Baddegama Wimalawansa Thero may not be immune to. Given the widespread environ- Mawatha, Colombo 10, Sri Lanka. mental pollution and the high proportions of global communities engaged in agriculture, CKDu may be the Received: 3 March 2017 Accepted: 14 June 2017 next global public health problem demanding attention. In Sri Lanka, the stage is now set to better understand References the burden, geographical distribution and trends of 1. Jayasekara KB, Dissanayake DM, Sivakanesan R, Ranasinghe A, Karunarathna RH, Priyantha Kumara GW. Epidemiology of chronic kidney disease, with CKDu and the country is on the road to solve the special emphasis on chronic kidney disease of uncertain etiology, in the mystery of ‘u’ in CKDu and contribute to the global North Central region of Sri Lanka. J Epidemiol. 2015;25(4):276–80. doi:10. knowledge on CKDu. 2188/jea.JE20140074. Accessed 2 June 2017. 2. 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Chronic kidney disease: global rising burden due to CKDu and other non-communicable dimension and perspectives. Lancet. 2013;382:260–72. http://dx.doi.org/10. diseases, a reform of the health services toward promotion 1016/S0140-6736(13)60687-X. Accessed 8 June 2017. 5. Athuraliya NTC, Abeysekara TDJ, Amerasinghe PH, Kumarasiri R, Bandara P, of wellbeing and prevention of ill health in populations is Karunaratne U, et al. Uncertain etiologies of proteinuric chronic kidney disease necessary to reduce the burden in the long run. Adoption in rural Sri Lanka. Kidney Int. 2011;80:1212–21. doi:10.1038/ki.2011.258. Kumaresan and Seneviratne Globalization and Health (2017) 13:43 Page 4 of 4

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